Our steps toward subcutaneous transplantation of macro-encapsulated islets

Background: Diabetes mellitus (DM) can be cured or greatly ameliorated by adequate insulin secretion from a relatively small volume of insulin-producing cells. Cell encapsulation enables allo- and even xeno-geneic cell therapy without immunosuppression. However, recent clinical trials show that micro-encapsulated islets are not fully retrievable after transplantation. By contrast, macro-encapsulated islets can be retrieved when necessary. As to the transplantation site, subcutaneous tissue can be promising, if new strategy can overcome the hypoxic status due to hypovascularity. In this review article, we summarized the development of macro-encapsulated islets and approaches toward subcutaneous transplantation in our laboratory over more than two decades. Our results repeatedly show that islets and encapsulated islets can be transplanted in various sites including subcutaneous tissue after pretreatment of neovascular induction. As to macro-encapsulation devices, our laboratory firstly developed mesh-reinforced poly-vinyl alcohol (PVA) hydrogel tubes and bags; agarose-based encapsulation methods followed. After that, PVA macro-encapsulated islets were developed utilizing sol-gel transition of PVA solution through micro-crystallization, induced by freezing and thawing. Recently, we took advantage of the excellent histocompatibility of ethylene vinyl alcohol co-polymer (EVOH) to fabricate the highly porous EVOH bag. A unique macro-encapsulation ㄎdevice using thermosensitive chitosan-based gel in combination with the EVOH bag was developed. Most recently, we found that slow release of hepatocyte growth factor (HGF) from the chitosan gel can protect islets against initial hypoxic status and subsequently induce neovascularization in subcutaneous tissue to exert islet function, eliminating the necessity for neovascularization pretreatment.
Conclusions: Our recent study showed that retrievable and replaceable macro-encapsulated islets can be transplanted subcutaneously without pretreatment. Although further improvements may be necessary, this immunosuppression-free approach may replace intraportal islet transplantation in the near future.